Myocardial Smad4 is essential for cardiogenesis in mouse embryos
Myocardial Smad4 is essential for cardiogenesis in mouse embryos
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DOI：
10.1161/circresaha.107.155630
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发表时间：
2007-08-03
影响因子：
20.1
通讯作者：
Jiao, Kai
中科院分区：
文献类型：
--
作者：
Song, Lanying;Yan, Wensheng;Jiao, Kai
先天性心脏病是最常见的人类出生缺陷，是婴儿发病率和死亡率的主要原因。越来越多的证据表明，转化生长因子-β/骨形态发生蛋白信号通路在心脏发生过程中起着关键作用。Smad 4编码哺乳动物中唯一常见的Smad蛋白，其是转化生长因子-β/骨形态发生蛋白信号传导的关键核介质。本研究的目的是探讨Smad 4在心脏发育过程中的作用。为了克服Smad 4（-/-）小鼠的早期胚胎致死性，我们使用Cre/loxP系统特异性地破坏心肌中的Smad 4。我们发现，心肌特异性Smad 4失活导致心力衰竭和胚胎在妊娠中期死亡。组织学分析显示，突变小鼠表现出细胞减少的心肌壁缺陷，这可能是心力衰竭的主要原因。细胞增殖减少和细胞凋亡增加均导致突变小鼠心肌壁缺陷。这篇文章中的数据与以前的报告相矛盾，该报告表明Smad 4对心脏发育有促进作用。我们进一步的分子表征表明，Nmyc及其下游靶点，包括细胞周期蛋白D1，细胞周期蛋白D2和Id 2的表达在突变胚胎中下调。报告分析表明，351-bp的Nmyc启动子的转录活性可以通过骨形态发生蛋白刺激正向调节和通过转化生长因子-β刺激负向调节。染色质免疫沉淀分析显示，Nmyc启动子可以与Smad 4形成复合物，表明Nmyc是Smad 4的直接下游靶标。总之，这项研究提供了第一个小鼠模型，表明Smad 4在心脏发生过程中发挥重要作用。
Congenital heart diseases are the most commonly observed human birth defects and are the leading cause of infant morbidity and mortality. Accumulating evidence indicates that transforming growth factor-beta/bone morphogenetic protein signaling pathways play critical roles during cardiogenesis. Smad4 encodes the only common Smad protein in mammals, which is a critical nuclear mediator of transforming growth factor-beta/bone morphogenetic protein signaling. The aim of this work was to investigate the roles of Smad4 during heart development. To overcome the early embryonic lethality of Smad4(-/-) mice, we specifically disrupted Smad4 in the myocardium using a Cre/loxP system. We show that myocardial-specific inactivation of Smad4 caused heart failure and embryonic lethality at midgestation. Histological analysis revealed that mutant mice displayed a hypocellular myocardial wall defect, which is likely the primary cause for heart failure. Both decreased cell proliferation and increased apoptosis contributed to the myocardial wall defect in mutant mice. Data presented in this article contradict a previous report showing that Smad4 is dispensable for heart development. Our further molecular characterization showed that expression of Nmyc and its downstream targets, including cyclin D1, cyclin D2, and Id2, were downregulated in mutant embryos. Reporter analysis indicated that the transcriptional activity of the 351-bp Nmyc promoter can be positively regulated by bone morphogenetic protein stimulation and negatively regulated by transforming growth factor-beta stimulation. Chromatin immunoprecipitation analysis revealed that the Nmyc promoter can form a complex with Smad4, suggesting that Nmyc is a direct downstream target of Smad4. In conclusion, this study provides the first mouse model showing that Smad4 plays essential roles during cardiogenesis.